title: Host defense mechanism-based rational design of live vaccine.
abstract: Live attenuated vaccine (LAV), mimicking natural infection, provides an excellent protection against microbial infection. The development of LAV, however, still remains highly empirical and the rational design of clinically useful LAV is scarcely available. Apoptosis and caspase activation are general host antiviral responses in virus-infected cells. Utilizing these tightly regulated host defense mechanisms, we present a novel apoptosis-triggered attenuation of viral virulence as a rational design of live attenuated vaccine with desired levels of safety, efficacy, and productivity. Mutant influenza viruses carrying caspase recognition motifs in viral NP and the interferon-antagonist NS1 proteins were highly attenuated both in vitro and in vivo by caspase-mediated cleavage of those proteins in infected cells. Both viral replication and interferon-resistance were substantially reduced, resulting in a marked attenuation of virulence of the virus. Despite pronounced attenuation, the viruses demonstrated high growth phenotype in embryonated eggs at lower temperature, ensuring its productivity. A single dose vaccination with the mutant virus elicited high levels of systemic and mucosal antibody responses and provided complete protection against both homologous and heterologous lethal challenges in mouse model. While providing a practical means to generate seasonal or pandemic influenza live vaccines, the sensitization of viral proteins to pathogen-triggered apoptotic signals presents a potentially universal, mechanism-based rational design of live vaccines against many viral infections.
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Yo Han
authors.initials: YH
authors.lastname: Jang
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Byun
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Lee
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Park
authors.forename: Yun Ha
authors.initials: YH
authors.lastname: Lee
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jinhee
authors.initials: J
authors.lastname: Lee
authors.forename: Kyun-Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Baik Lin
authors.initials: BL
authors.lastname: Seong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D005260:Female; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D059372:Nucleotide Motifs / Q000235:genetics; D010063:Ovum / Q000821:virology; D059748:Proteolysis; D014613:Vaccines, Attenuated / Q000276:immunology; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D014613:Vaccines, Attenuated; D014764:Viral Proteins; D014765:Viral Vaccines; D020169:Caspases